U.S. patent number 5,543,156 [Application Number 08/184,770] was granted by the patent office on 1996-08-06 for bioerodible devices and compositions for diffusional release of agents.
This patent grant is currently assigned to Alza Corporation. Invention is credited to Estela Basso, Fred P. Ehnow, Sharon M. Fujita, Wouter E. Roorda, Karly S. Wang.
United States Patent |
5,543,156 |
Roorda , et al. |
August 6, 1996 |
Bioerodible devices and compositions for diffusional release of
agents
Abstract
The present invention is directed to erodible delivery devices
and to the compositions comprising the devices. The devices
comprise (a) a body formed of a bioerodible polymer or polymers
together with a required excipient not generally considered to be a
pore-former ("required excipient"), and (b) an active agent. The
agent is released from the device at a controlled rate and in a
therapeutically effective amount, with the rate being primarily
independent of the erosion rate of the polymer. The rate of release
of the active agent from the polymeric compositions of the present
invention is significantly increased over the rate of release
dependent on erosion of the polymer matrix. The invention makes
possible the increased control over and improved reproducibility of
the release profile of the agent from the polymer. The invention is
further directed to a method of delivering to an environment of use
an active agent, which method comprises placing an appropriately
sized and shaped delivery device of the above description in the
environment of use.
Inventors: |
Roorda; Wouter E. (Newark,
CA), Ehnow; Fred P. (San Carlos, CA), Basso; Estela
(Santa Clara, CA), Wang; Karly S. (Newark, CA), Fujita;
Sharon M. (Berkeley, CA) |
Assignee: |
Alza Corporation (Palo Alto,
CA)
|
Family
ID: |
27093714 |
Appl.
No.: |
08/184,770 |
Filed: |
January 21, 1994 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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984388 |
Dec 1, 1992 |
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709862 |
Jun 14, 1991 |
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641222 |
Jan 9, 1991 |
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Current U.S.
Class: |
424/484; 424/426;
424/428; 424/444; 424/468; 424/486; 424/499; 424/501 |
Current CPC
Class: |
A61K
9/2013 (20130101); A61K 9/204 (20130101); A61K
9/7007 (20130101) |
Current International
Class: |
A61K
9/20 (20060101); A61K 9/70 (20060101); A61K
009/10 (); A61K 009/14 (); A61K 009/22 (); A61K
009/70 () |
Field of
Search: |
;424/484,426,428,486,444,499,501,468 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Plastic Encyclopedia, vol. 46, pp. 62 to 70 (1969)..
|
Primary Examiner: Webman; Edward J.
Attorney, Agent or Firm: Dillahunty; Mary Ann Ito; Richard
T. Stone; Steven F.
Parent Case Text
REFERENCE TO RELATED APPLICATION
This application is a continuation of application Ser. No.
07/984,388, filed Dec. 1, 1992, abandoned and benefit of the filing
date of said earlier filed application is claimed number 35 U.S.C.
.sctn.120, which is a continuation of application Ser. No.
07/709,862, filed Jun. 14, 1991, now abandoned, which is a
continuation-in-part of application Ser. No. 07/641,222, filed Jan.
9, 1991, abandoned.
Claims
What is claimed is:
1. A device for delivering a pharmaceutically active agent to an
animal at a controlled rate over a prolonged period of time,
wherein the device comprises:
(a) a body, shaped, sized and adapted for delivering a
pharmaceutically active agent to the animal, the body
comprises:
(i) 29-86 wt % of bioerodible polymer, a copolymer of bioerodible
polymers, or a mixture of bioerodible polymers, and
(ii) 14-71 wt % of a hydrophobic compound, the hydrophobic compound
being selected from the group consisting of stearates, phosphates,
.beta.-carotene, zeazanthin, cholesterol and 5,6-cholestene;
and
(b) a therapeutically effective amount of the agent to be
delivered; wherein the body is characterized by the delivery rate
of the agent to be delivered from the matrix being greater when the
body comprises (i) and (ii) than when the body comprises (i).
2. A device according to claim 1 wherein the hydrophobic compound
is cholesterol and the bioerodible polymer is a poly(orthoester)
polymer, a poly(lactic acid) polymer, a poly(glycolic acid) polymer
or a copolymer of lactic acid and glycolic acid.
3. A device according to claim 2 wherein the polymeric matrix
further comprises 5-35 wt % lactose.
4. A device according to claim 1 wherein the hydrophobic compound
is cholesterol and the bioerodible polymer is a poly(orthoester)
polymer.
5. A device according to claim 1 wherein the hydrophobic compound
is cholesterol, calcium stearate or calcium phosphate and the
bioerodible polymer is a copolymer of lactic acid and glycolic
acid.
6. A composition of matter useful as an erodible matrix material
for delivering a pharmaceutically active agent the composition of
matter comprising:
(a) 29-86 wt % bioerodible polymer, a copolymer of bioerodible
polymers, or a mixture of bioerodible polymers; and
(b) 14-71 wt % of a hydrophobic compound, the hydrophobic compound
being selected from the group consisting of stearates, phosphates,
.beta.-carotene, zeazanthin, and cholesterol wherein the matrix
material is charactered by a delivery rate of the agent to be
delivered from the matrix being greater when the matrix comprises
(i) and (ii) than when the matrix comprises (i).
7. A composition according to claim 6 wherein the hydrophobic
compound is cholesterol and the bioerodible polymer is a
poly(orthoester) polymer, a poly(lactic acid) polymer, a
poly(glycolic acid) polymer or a copolymer of lactic acid and
glycolic acid.
8. A composition according to claim 6 wherein the hydrophobic
compound is cholesterol and the bioerodible polymer is a
poly(orthoester) polymer.
9. A composition according to claim 6 wherein the hydrophobic
compound is cholesterol, calcium stearate or calcium phosphate and
the bioerodible polymer is a copolymer of lactic acid and glycolic
acid.
10. A method for delivering a pharmaceutically active agent to an
animal at a controlled rate and over a prolonged period of time,
which method comprises placing a delivery device in the animal,
wherein the delivery device is comprised of:
(a) a shaped body, sized and adapted for delivering a
pharmaceutically active agent to the animal, the body formed of an
erodible, release rate-controlling matrix material, where the
matrix material comprises:
(i) 29-86 wt % bioerodible polymer, a copolymer of bioerodible
polymers, or a mixture of bioerodible polymers, and
(ii) 14-71 wt % of a hydrophobic compound, the hydrophobic compound
being selected from the group consisting of stearates, phosphates,
.beta.-carotene, zeazanthin, cholesterol, and 5,6-cholestene;
and
(b) A therapeutic amount of the agent to be delivered, wherein the
delivery rate of the agent being greater when the matrix comprises
(i) and (ii) than when the matrix comprises (i).
11. A method according to claim 10 wherein the hydrophobic compound
is cholesterol and the bioerodible polymer is a poly(orthoester)
polymer, a poly(lactic acid) polymer, a poly(glycolic acid) polymer
or a copolymer of lactic acid and glycolic acid.
12. A method according to claim 11 wherein the polymeric matrix
further comprises 5-35 wt % lactose.
13. A method according to claim 10 wherein the hydrophobic compound
is cholesterol and the bioerodible polymer is a poly(orthoester)
polymer.
14. A method according to claim 10 wherein the hydrophobic compound
is cholesterol, calcium stearate or calcium phosphate and the
bioerodible polymer is a copolymer of lactic acid and glycolic
acid.
15. A method for increasing the rate of release of a
pharmaceutically active agent to an animal from a bioerodible
polymeric matrix over time and primarily independent of the rate of
erosion of the polymeric matrix, which method comprises:
(a) mixing a polymeric matrix, comprising
(i) 29-86 wt % bioerodible polymer, a copolymer of bioerodible
polymers, or a mixture of bioerodible polymers, with
(ii) 14-71 wt % of a hydrophobic compound, the hydrophobic compound
being selected from the group consisting of stearates, phosphates,
.beta.-carotene, zeazanthin, cholesterol and 5,6-cholestene;
(b) incorporating a therapeutically effective amount of the agent
into the polymeric matrix wherein the matrix is characterized by
the delivery rate of the agent to be delivered from the matrix
being greater when the matrix comprises (i) and (ii) than when the
matrix comprises (i).
16. A method according to claim 15 wherein the hydrophobic compound
is cholesterol and the bioerodible polymer is a poly(orthoester)
polymer, a poly(lactic acid) polymer, a poly(glycolic acid) polymer
or a copolymer of lactic acid and glycolic acid.
17. A method according to claim 16 wherein the polymeric matrix
further comprises 5-35 wt % lactose.
18. A method according to claim 15 wherein the hydrophobic compound
is cholesterol and the bioerodible polymer is a poly(orthoester)
polymer.
19. A method according to claim 15 wherein the hydrophobic compound
is cholesterol, calcium stearate or calcium phosphate and the
bioerodible polymer is a copolymer of lactic acid and glycolic
acid.
20. A method for increasing the rate of release of a
pharmaceutically active agent to an animal from a bioerodible
polymeric matrix over time, which method comprises:
(a) incorporating the agent, in a therapeutically effective amount,
into the polymeric matrix, which matrix is comprised of:
(i) 29-86 wt % bioerodible polymer, a copolymer of bioerodible
polymers, or a mixture of bioerodible polymers, and
(ii) 14-71 wt % of a hydrophobic compound, the hydrophobic compound
being selected from the group consisting of stearates, phosphates,
.beta.-carotene, zeazanthin, cholesterol, or 5,6-cholestene;
and
(b) placing the polymeric matrix containing the agent in the animal
wherein the matrix is characterized by the delivery rate of the
agent to be delivered from the matrix being greater when the matrix
comprises (i) and (ii) than when the matrix comprises (i).
21. A method according to claim 20 wherein the hydrophobic compound
is cholesterol and the bioerodible polymer is a poly(orthoester)
polymer, a poly(lactic acid) polymer, a poly(glycolic acid) polymer
or a copolymer of lactic acid and glycolic acid.
22. A method according to claim 21 wherein the polymeric matrix
further comprises 5-35 wt % lactose.
23. A method according to claim 20 wherein the hydrophobic compound
is cholesterol and the bioerodible polymer is a poly(orthoester)
polymer.
24. A method according to claim 20 wherein the hydrophobic acid is
cholesterol, calcium stearate or calcium phosphate and the
bioerodible polymer is a copolymer of lactic acid and glycolic
acid.
25. A method for providing improved reproducibility of the release
profile of a pharmaceutically active agent to an animal from a
bioerodible polymeric matrix over time, where the release profile
of the agent is primarily independent of the rate of erosion of the
polymeric matrix, which method comprises:
(a) incorporating the agent, in a therapeutically effective amount,
into the polymeric matrix, which matrix is comprised of:
(i) 29-86 wt % bioerodible polymer, a copolymer of bioerodible
polymers, or a mixture of bioerodible polymers, and
(ii) 14-71 wt % of a hydrophobic compound, the hydrophobic compound
being selected from the group consisting of stearates, phosphates,
.beta.-carotene, zeazanthin, cholesterol, or 5,6-cholestene;
and
(b) placing the polymeric matrix containing the agent in the animal
wherein the matrix is characterized by the delivery rate of the
agent to be delivered from the matrix being greater when the matrix
comprises (i) and (ii) than when the matrix comprises (i).
26. A method according to claim 25 wherein the hydrophobic compound
is cholesterol and the bioerodible polymer is a poly(orthoester)
polymer, a poly(lactic acid) polymer, a poly(glycolic acid) polymer
or a copolymer of lactic acid and glycolic acid.
27. A method according to claim 26 wherein the polymeric matrix
further comprises 5-35 wt % lactose.
28. A method according to claim 25 wherein the hydrophobic compound
is cholesterol and the bioerodible polymer is a poly(orthoester)
polymer.
29. A method according to claim 25 wherein the hydrophobic acid is
cholesterol, calcium stearate or calcium phosphate and the
bioerodible polymer is a copolymer of lactic acid and glycolic
acid.
Description
FIELD OF THE INVENTION
This invention pertains to bioerodible polymers and delivery
devices made of bioerodible polymers. More particularly, this
invention relates to bioerodible polymers useful for the delivery
of an active agent, including those agents that do not normally
diffuse from a polymer, the delivery being primarily independent of
the erosion rate of the polymer.
BACKGROUND OF THE INVENTION
Bioerodible polymers are well known in the art, and the importance
of delivery devices manufactured from such polymers has been long
recognized. Such devices are valuable because they can contain a
beneficial or otherwise active agent that, as the polymer erodes,
is delivered at a controlled rate and in an effective amount to the
environment of use.
One such family of polymers are the poly(orthoesters) disclosed in
U.S. Pat. Nos. 4,070,347, 4,093,709, 4,122,158, 4,131,648,
4,138,344, and 4,155,992, for example. Other polymers are the
poly(orthoesters) and poly(orthocarbonates) disclosed in U.S. Pat.
No. 4,180,646. A third group of bioerodible polymers are the
poly(lactic acids) and the poly(glycolic acids) and mixtures and
copolymers thereof. All of these polymers have a controlled rate of
erosion to innocuous products when in an aqueous or a biological
environment.
Many active agents are released from these bioerodible polymers
primarily by dissolution or erosion of the polymer. This is
especially true of those agents which, because of high molecular
weight or low solubility, for example, do not readily diffuse from
a polymer matrix. However, release of beneficial agents by erosion
may be undesirable or unaccceptable in many applications because
the agent is not released or is released at an insufficient rate
for a substantial period of time until erosion of the polymer has
begun, and is thus unavailable to the environment for that extended
"lag phase" period. Additionally, release through erosion of the
polymer is a problem if it is desirable to have a rate of release
of the agent which is different from the rate of erosion of the
polymer, since release is normally dependent on the erosion rate of
the polymer. Also, erosion of the polymer is not always continuous
or predictable, so that the reproducibility of a release rate
profile is often difficult.
Even where an agent is released from a bioerodible polymer by
dissolution in and diffusion from the polymer, such diffusional
release is often a slow process and not easily controlled. In
general, the use of fillers in the polymeric matrix will slow this
process. Additionally, the dissolution rate can be disturbed if the
polymer loses its shape, which often happens with certain polymers
when they are placed in a particular environment.
Therefore, it would be desirable to provide a means for controlling
the delivery of an agent from a bioerodible polymer and to provide
a reproducible release rate profile for the agent.
SUMMARY OF THE INVENTION
The present invention is directed to erodible delivery devices and
to the compositions comprising the devices. The devices comprise
(a) a body formed of a bioerodible polymer or polymers together
with a required excipient not generally considered to be a
pore-former ("required excipient"), and (b) an active agent. The
agent is released from the device at a controlled rate and in a
therapeutically effective amount, with the rate being primarily
independent of the erosion rate of the polymer. The rate of release
of the active agent from the polymeric compositions of the present
invention is significantly increased over the rate of release from
the polymer matrix without the required excipient, and the
reproducibility of release from the compositions of the invention
is substantially improved. The composition body of the device may
optionally also include one or more pore-former materials.
The invention also concerns compositions comprising a bioerodible
polymer or polymers and an excipient not generally considered to be
a pore-former ("required excipient"). The composition may also
optionally include one or more pore-former materials.
The invention is further directed to a method of delivering to an
environment of use an active agent, including those that do not
normally diffuse from a polymeric matrix, which method comprises
placing an appropriately sized and shaped delivery device of the
above description in the environment of use.
DESCRIPTION OF THE DRAWINGS
FIG. 1 shows graphically the cumulative percent release of lysozyme
in vitro from a matrix according to the present invention and from
a control matrix.
FIG. 2 shows graphically the cumulative percent release of lysozyme
in vitro from a matrix according to the present invention which
includes, in addition, lactose, and from a control matrix.
FIG. 3 shows graphically the cumulative percent release of lysozyme
in vitro from devices of the present invention, the devices shaped
either as sheets (FIG. 3a) or as rods (FIG. 3b).
FIG. 4 shows graphically the release rates of lidocaine from
devices of the present invention containing varying amounts of
cholesterol.
FIG. 5 shows graphically the release rates of lysozyme from control
devices that do not contain a required excipient.
FIG. 6 shows graphically the release rates of lysozyme from devices
of the present invention containing cholesterol.
FIG. 7 shows graphically the release rates of lysozyme from devices
of the present invention containing calcium stearate.
FIG. 8 shows graphically the release rates of lysozyme from devices
of the present invention containing calcium phosphate.
FIG. 9 shows graphically the release rates of lysozyme from control
devices that do not contain a required excipient.
FIG. 10 shows graphically the release rates of lysozyme from
devices of the present invention containing cholesterol.
FIG. 11 shows graphically the release rates of lysozyme from
devices of the present invention containing calcium stearate.
FIG. 12 shows graphically the release rates of lysozyme from
devices of the present invention containing calcium phosphate.
DETAILED DESCRIPTION OF THE INVENTION
The active agent delivery devices of this invention provide several
important advantages over previously known delivery systems. The
devices provide for a bioerodible matrix system capable of
providing a rate of release of an active agent from the system that
is primarily independent of the rate of erosion of the polymer
matrix. Also, the rate of release may be regulated by varying the
amount of required excipient that is included in the matrix.
Additionally, the active agent is released from the device of the
invention at a rate that is significantly increased over the
release rate of the agent from a bioerodible polymeric device that
does not include the required excipient. Also, the release of the
agent may occur during the lag phase of the bioerodible polymer.
Thus, the invention makes possible the increased control over, as
well as greater reproducibility of, the release profile of the
agent from the polymer.
The release rate of an active agent from the system of the
invention is primarily independent of the rate of erosion of the
polymer matrix. What is meant herein by this is that, although
there will likely be at least some erosion of the matrix during the
useful life of the system so that a certain amount of the agent may
be released as a result of such erosion, release of a significant
amount, and usually substantially all of the agent can be achieved
from the system of the invention without being dependent on the
rate of erosion of the matrix.
As used herein, the terms an active agent or a drug which "does not
normally diffuse" or "is normally non-diffusing" from a polymeric
matrix refer to an active agent or a drug which under normal
circumstances is incapable of being sufficiently released from a
polymeric matrix by dissolution in the polymeric matrix and
diffusion through and out of the matrix.
As used herein, the terms "therapeutically effective" amount or
rate refer to the amount or rate of the active agent needed to
effect the desired therapeutic result.
The term "matrix", as used herein, denotes a solid phase carrier
within which the active agent can be dispersed. The carrier can be
any desired shape, such as sphere, spheroid, cylinder, rod, sheet,
and the like, or consistency, such as solid, malleable or
deformable, flowable, and the like.
The terms "active agent" and "drug" are used interchangeably herein
and refer to an agent, drug, compound or composition of matter
which provides some therapeutic, often beneficial, effect.
The matrix material is biocompatible (e.g., it should not be toxic
or otherwise cause adverse tissue reactions) and is bioerodible.
The term "bioerodible" is used herein to mean materials which are
degradable or erodible in vivo, either enzymatically or
non-enzymatically, to produce biocompatible or non-toxic
by-products, such as innocuous low molecular weight species. The
by-products can be further metabolized or excreted via normal
physiologic pathways. The matrix material is also noncarcinogenic
and causes no adverse immunological response.
Representative natural bioerodible materials include naturally
occurring polymers such as collagen, cross-linked collagen,
agar-agar, gelatin, cross-linked gelatin, and polysaccharides, for
example.
Examples of bioerodible synthetic polymers include, but are not
limited to, poly(lactic) acid and poly(glycolic acid) or their
derivatives; copolymers of lactic acid and glycolic acid;
polyamides; polyesters; poly(orthoesters); polycaprolactones;
polyanhydrides; and polyvinylpyrrolidones. Mixtures and
combinations of these may also be used.
One preferred type of bioerodible polymer comprises
poly(orthoesters). Suitable poly(orthoester) polymers can be
selected from those under the trademark Alzamer.RTM.. These
polymers are disclosed in U.S. Pat. Nos. 4,070,347, 4,093,709,
4,122,158, 4,131,648, 4,138,344, and 4,155,992, for example, all of
which are incorporated herein by reference. In a presently
preferred embodiment, the polymers as used in this invention are
based upon two Alzamer poly(orthoesters): 1)
poly(2,2-dioxy-cis,trans-1,4-cyclohexane dimethylene
tetrahydrofuran), which is a hard solid (glassy) polymer having the
following structure (A): ##STR1## where m equals a number such that
the molecular weight of the polymer (A) is within the range of
1,000 to 100,000; and 2) poly(2,2-dioxy-1,6-hexamethylene
tetrahydrofuran), which is a viscous polymeric liquid having the
following structure (B): ##STR2## where n equals a number such that
the molecular weight of the polymer (B) is within the range of
1,000 to 100,000.
Other orthoester polymers with similar physical properties can be
substituted for the polymers noted above, and are disclosed in, for
example, U.S. Pat. No. 4,180,646, which is incorporated herein by
reference.
The bioerodible polymers useful in the present invention may also
be chosen, for instance, from the poly(lactic acids) or the
poly(glycolic acids) or copolymers of lactic acid and glycolic
acid. Such polymers and copolymers are well known in the art and
are well documented in the literature.
The polymeric matrix of the present invention may be selected from
the group consisting of a homopolymer, physical mixtures of two or
more polymers, and copolymers of two or more polymers. Methods for
preparing these are known in the art or are described in the
above-incorporated patents. In a presently preferred embodiment,
the matrix is chosen from poly(orthoester) polymer (A) or a
physical mixture of poly(orthoester) polymers (A) and (B).
The required excipient, which is a necessary component in the
erodible polymeric matrix of the present invention, is an excipient
that is not normally considered in the polymer arts to be a
pore-former and yet provides a means for an active agent, including
a normally non-diffusing agent, to be released from the matrix in a
manner primarily independent of the erosion of the matrix and
during the lag phase of the polymer. The required excipient can be
chosen from, for example, hydrophobic compounds. Hydrophobic
compounds which may be useful in the present invention include, but
are not limited to, stearates such as calcium stearate, magnesium
stearate, and aluminum stearate; phosphates such as calcium
phosphate; myricyl cerotate; .beta.-carotene; zeaxanthin; and
cholesterol (3-hydroxy-5,6-cholestene) and related compounds such
as 3-amino-5,6-cholestene and other related analogs,
5,6-cholestene, and cholestane and related analogs such as
3-hydroxy-cholestane.
Cholesterol has been previously used as a structural component or a
filler, but not as an agent to increase release rates or improve
the reproducibility of release rates. For example, cholesterol can
be a structural component of a liposome, providing a close-packed
lipid structure to the liposome and slowing down the rate of
release of the active agent. Cholesterol can be used as a filler in
polymer matrices or can be added to matrices to modify the rate of
controlled release of agent therefrom. In these prior uses, the
presence of cholesterol was shown to either not affect the rate of
release of agent or to slow down or decrease the rate of release of
agent, with the release rate decreasing as the amount of
cholesterol present is increased. This is consistent with the
general belief in the polymer arts that fillers generally tend to
slow the release of an agent.
Surprisingly, it has now been found that not only does the presence
of cholesterol in the bioerodible matrix of the present invention
allow an active agent to be released from the matrix at a rate that
is primarily independent of the erosion rate of the matrix, but it
also allows the agent to be released at a rate that is
significantly greater than the release rate from such a matrix that
does not include cholesterol. Additionally, and again surprisingly,
the rate of release is increased as the amount of cholesterol in
the polymeric matrix is increased.
It has also been found that the presence of cholesterol in the
bioerodible matrix provides greatly improved reproducibility of the
rate release profile of an active agent from the matrix.
The amount of the required excipient used for the present purpose
will be dependent on several factors, such as the actual excipient
used, the chosen polymeric component(s), the particular active
agent to be released, the desired release rate and duration of
release of the agent, and the body site at which the device is to
be placed. Generally, the amount of required excipient is from
about 1% to about 60% by weight (wt %) of the device. When
cholesterol is used as the required excipient, the cholesterol may
be present in an amount of from about 1 to about 50 wt % or higher,
and preferably in an amount of from about 1 to about 35 wt %. As
the amount of required excipient is increased in the matrix
composition, the faster the active agent is released from the
matrix system.
The present invention has been found to be useful for delivering a
wide variety of active agents to the environment of use. In
addition to those agents which are released from a bioerodible
polymer by diffusion from a polymeric matrix, it has now
surprisingly been found that agents which may be used in the
present invention can include an agent that does not, under normal
circumstances, diffuse from a polymeric matrix. Such an agent
either cannot be released from the matrix at all or is released
only as the matrix erodes and breaks apart. Such an agent may be
normally non-diffusing for any one or more of a variety of reasons.
For example, the agent may have too high a molecular weight and
thus it becomes entrapped within the matrix structure, it may have
a low solubility so that it cannot readily diffuse through the
matrix, or it may have a low diffusion coefficient.
Exemplary agents that can be delivered according to this invention
are those that are compatible with the polymeric matrix and with
the required excipient and include, among others, biocides,
sterilization agents, food supplements, nutrients, vitamins, sex
sterilants, fertility inhibitors, and fertility promoters. They can
include drugs that act on the peripheral nerves, adrenergic
receptors, cholinergic receptors, nervous system, skeletal muscles,
cardiovascular system, smooth muscles, blood circulatory system,
synoptic sites, neuroeffector junctional sites, endocrine and
hormone systems, immunological system, reproductive system,
skeletal system, autocoid systems, alimentary and excretory
systems, histamine system, and central nervous system. Suitable
agents may be selected from, for example, proteins, enzymes,
hormones, polynucleotides, nucleoproteins, polysaccharides,
glycoproteins, lipoproteins, polypeptides, steroids, analgesics,
local anesthetics, antibiotic agents, anti-inflammatory
corticosteroids, ocular drugs, and synthetic analogs of these
molecules.
Peptides and polypeptides which are suitable for use in this
invention include, but are not limited to, insulin; glucagon;
thyroid stimulating hormone; parathyroid and pituitary hormones;
calcitonin; renin; prolactin; corticotrophin; thyrotropic hormone;
follicle stimulating hormone; chorionic gonadotropin; gonadotropin
releasing hormone; somatropin; somatotropin; oxytocin; vasopressin;
prolactin; somatostatin; lypressin; pancreozymin; luteinizing
hormone; interferons; interleukins; growth hormones such as human
growth hormone, bovine growth hormone and porcine growth hormone;
fertility inhibitors such as the prostaglandins; fertility
promoters; growth factors; and human pancreas growth hormone
releasing factor. Enzymes suitable for use include, but are not
limited to, hydrolases, transferases, proteases, ligases,
isomerases, lysases such as lysozyme, and the oxidoreductases such
as esterases, phosphatases, glycosidases, and peptidases. Also
capable of delivery from the device of this invention are bovine
serum albumin, human serum albumin, proalbumin, unsecreted
adrenocorticotrophin, thyroglobulin, soybean trypsin inhibitor,
alkaline phosphatase, and catalase. Exemplary steroids useful in
the invention include, but are not limited to, sterols; cardiac
glycosides such as digitoxin, digoxin, and ouabain; corticosteroids
such as hydrocortisone, hydrocorticosterone acetate, cortisone
acetate and triamcinolone; and sex hormones such as testosterone,
the estrogens, including 17.beta.-estradiol and ethinyl estradiol,
and the progestins, including progesterone, prednisolone,
gestodene, levonorgestrel, ST-1435 and norethindrone. Local
anesthetics useful in the invention include, but are not limited
to, procaine, lidocaine, piperocaine, tetracaine, bupivacaine,
dibucaine, mepivacaine, cocaine, benzocaine, their hydrochloride
salts, and the like. Analgesics useful herein include, but are not
limited to, morphine, codeine, meperidine, and nalorphine.
Antibiotics include, but are not limited to, penicillins,
cephalosporins, vancomycin, bacitracin, cycloserine, polymyxins,
colistin, nystatin, tetracyclines, chloramphenicol, metronidazole,
neomycin, streptomycin, kanamycin, erythromycin, and gentamicin.
Antipyretics and anti-inflammatory agents include, but are not
limited to, aspirin, indomethacin, salicylamide, naproxen,
colchicine, ketoprofen, piroxicam, fenoprofen, diclofenac, and
indoprofen. Ocular drugs include, but are not limited to, timolol,
timolomaleate, pilocarpine, atropine, scopolamine and eserine
salicylate. Muscle relaxants and antiparkinson agents include, but
are not limited to, mephenesin, methocarbomal, levodopa/carbidope,
and biperiden.
The active agent can be present in the invention in the various
chemical and physical forms such as uncharged molecules, molecular
complexes, and pharmacologically acceptable acid addition and base
addition salts such as hydrochlorides, hydrobromides, sulfate,
laurylate, palmitate, phosphate, nitrate, borate, acetate, maleate,
tartrate, oleate and salicylate. For acidic compounds, salts of
metals, amines or organic cations can be used. Derivatives of
agents such as esters, ethers and amides can be used. An active
agent can be used alone or mixed with other active agents.
The lists of active agents recited above are given only to
illustrate the types of active agents which are suitable for use in
practicing the invention, and are not intended to be
exhaustive.
The amount of active agent employed in the delivery device will be
that amount necessary to deliver a therapeutically effective amount
of the agent to achieve the desired result at the site of
application. In practice, this will vary depending upon the
particular agent, the severity of the condition, and the desired
effect, as well as the desired rate and duration of release.
In addition to the polymer, the required excipient and the active
agent, the devices of this invention may also include, if desired,
one or more diluents; vehicles; stabilizers such as potassium
phosphate, sodium phosphate, sodium carbonate or magnesium
hydroxide; dyes; inert fillers; pigments; and other components of
polymeric matrix systems as are known in the art.
In one preferred embodiment, the device includes a hydrophilic
pore-former such as lactose to provide an even greater release rate
of agent from the matrix, when such increased release rate is
desired. Generally, the hydrophilic pore-former is present in an
amount of from about 1 wt % to about 50 wt %, preferably from about
5 wt % to about 35 wt %.
The devices of the invention can be manufactured by standard
techniques. For example, the polymers with the required excipient
and the agent mixed therewith can be extruded into filaments, spun
into fibers, pressed into shaped articles, solvent film cast,
doctor-bladed into thin films, coated by solvent evaporation,
coated by using a fluidized bed, compression molded, transfer
molded, formed into microparticles by coacervation or cryogrinding
or solvent evaporation for example, and like methods of
manufacture.
The devices can be a single matrix, a container with a reservoir
therein, or a number of layers, for example. The devices can be
made into various shapes such as flat, square, round, tubular,
disc, ring, and the like. Presently preferred embodiments are
films, rods, and particles. Also, the devices of the invention are
sized, shaped and adapted for implantation, insertion, placement,
depositing or spreading on the body, in the body, or in cavities
and passageways of the body of an animal. Standard procedures for
processing the polymer, the required excipient and the agent are
known in the art or are described in Plastic Encyclopedia, Vol. 46,
pp 62 to 70 (1969) and in the patents cited supra.
In the practice of the present invention, the device of the
invention is placed in or on the environment of use. In the
presently preferred embodiments, the environment of use is the body
of an animal. Included in the term "animal" are humans, primates,
mammals, domesticated or semi-domesticated animals (such as
household, pet, and farm animals), laboratory animals (such as
mice, rats and guinea pigs), birds, reptiles, fish, zoo animals,
and the like. The devices may be placed on or in wounds, spread as
a thin film, or injected as microparticles or as an implant into
the body, for example.
The following examples are set forth as representative and
illustrative of the spirit of the present invention. These examples
are not to be construed as limiting the scope of the invention in
any way.
EXAMPLE 1
The release profiles of the enzyme lysozyme (a high molecular
weight peptide compound) from a matrix according to the present
invention and from a prior art matrix were determined as
follows.
Lysozyme, potassium phosphate and cholesterol were each dried and
milled to a particle size of 5 microns. Fifty wt % of the polymer
poly(2,2-dioxy-cis,trans-1,4-cyclohexane dimethylene
tetrahydrofuran) (polymer (A)) having a molecular weight of 28,000,
35 wt % of cholesterol and 5 wt % of potassium phosphate were
hand-mixed together at 110.degree.-120.degree. C. for 10 min.
Lysozyme (10 wt %) was added, and mixing was continued for 5 min.
The mixture was then placed in a CSI miniextruder and mixing was
continued for 5 min. at 90.degree. C. It was then melt-pressed at
90.degree. C. into sheets which were die cut into 1.times.1 cm
squares, 0.25 mm thick.
Polymeric squares not containing cholesterol (the control) were
prepared in the same manner and had a composition of 85 wt %
polymer (A), 10 wt % lysozyme and 5 wt % potassium phosphate.
The squares were placed between two pieces of dialysis tubing and
clamped with two concentric teflon rings. Six squares were tested
from each formulation. Each square device held by the teflon rings
was immersed in release rate media (phosphate buffer, pH 7.2), and
the amount of lysozyme released into the buffer was measured at
selected intervals. After each measurement, the device was placed
in fresh media.
The cumulative percent release of the lysozyme from each of the two
formulations is presented in FIG. 1 and shows an increasing release
of the enzyme from the matrix containing the cholesterol and almost
no release of the enzyme from the noncholesterol-containing matrix
over a period of 7 days.
EXAMPLE 2
Following the procedures of Example 1, square devices were made
with the following composition: 50 wt % polymer (A) (Mw=28,000), 5
wt % potassium phosphate, 10 wt % lysozyme, 20 wt % cholesterol and
15 wt % lactose. The release of lysozyme was determined, in
comparison with the release from control devices (of the same
composition as the controls in Example 1).
The cumulative percent release of lysozyme (from six devices each)
was determined and is presented in FIG. 2.
EXAMPLE 3
Different shaped devices (sheets and rods) were prepared and tested
for lysozyme release, both in vivo and in vitro.
Preparation of the additives and mixing of the ingredients were
carried out following the procedures of Example 1. Two
formulations, listed in Table A below, were prepared.
TABLE A ______________________________________ Formulation
Composition (wt %) 1 2 ______________________________________
Polymer (A) 50 70 Lysozyme 10 10 Potassium phosphate 5 5
Cholesterol 35 15 ______________________________________
Sheets were prepared from each of Formulations 1 and 2 by
melting-pressing the mixture in a Carver press into 0.25 mm.times.1
cm.times.1 cm slabs. Rods from each formulation were prepared by
extruding the mixture into 2 mm diameter.times.1 cm length rods,
using a miniextruder. Weight of each sheet or rod was approximately
30 mg.
To determine the release rate of lysozyme from the devices in
vitro, each sheet or rod was placed in dacron mesh and held in
release media, following the procedures in Example 1.
To determine the release rate in vivo, both sheets and rods were
implanted subcutaneously in rats. For each time point, three
devices of each formulation and shape were implanted. Devices were
explanted from the rats at selected time points, and the residual
lysozyme remaining in each device was analyzed by HPLC after
hydrolyzing the polymer (by heat for 1 hour at 50.degree. C. with
1% HCl).
The cumulative percent release of lysozyme in vitro from each of
the two formulations is presented in FIG. 3. FIG. 3(a) shows the
release from the sheets and FIG. 3(b) shows the release from the
rods. The devices containing 35 wt % cholesterol released the
enzyme more quickly than those containing 15 wt % cholesterol, and
most of the lysozyme was released from formulation 1 before 5 days,
while formulation 2 released the lysozyme over about 9.5 days.
The cumulative release of lysozyme in vivo was greater in all cases
than the cumulative release in vitro, but in each case the release
in vivo proportionally followed basically the same release rate
profile as those of the in vitro release.
EXAMPLE 4
To determine the release of lidocaine (a low molecular weight
diffusional compound) from matrices of the invention, devices were
prepared following the procedures of Example 1 and having the
compositions indicated under Table B below.
TABLE B ______________________________________ Formulation
Composition (wt %) a b c d ______________________________________
Polymer (A) 70 60 45 20 Lidocaine 30 30 30 30 Cholesterol 0 10 25
50 ______________________________________
The matrices were each formed into a film of 0.25 mm thickness and
cut into 1 cm.times.1 cm squares. Each square was placed into 10.0
ml of pH 7.2 phosphate buffer release media and held at 37.degree.
C. in a shaking water bath. The release of the lidocaine from the
matrices into the media was measured at time intervals over a
period of 360 hours following the procedures of Example 1.
The results are presented in FIG. 4 and show that cholesterol can
be used to vary the release profile of a low molecular weight drug
such as lidocaine. They also show that the release of lidocaine
increased as the amount of cholesterol in the matrix was increased
above 10 wt %.
EXAMPLE 5
Following the procedures of Example 1, 1.times.1 cm square devices,
0.5 mm thick, were made having the following composition: 75 wt %
poly(lactic-glycolic) copolymer ("PLGA") (Resomer.RTM. 503,
Boehringer Ingelheim; 50:50 lactic acid:glycolic acid; intrinsic
viscosity 0.4.+-.10%; approx. 30,000 MW), 5 wt % lysozyme and 20 wt
% hydrophobic excipient. The hydrophobic excipients tested were
cholesterol, calcium stearate and calcium phosphate. Control
devices were composed of 95 wt % PLGA (Resomer 503) and 5 wt %
lysozyme. Certain of the devices were irradiated
(.beta.-irradiation) at 2.5 megarad. The in vitro release of
lysozyme through human cadaver skin was determined (n=3 devices)
and the percent release of the various devices is presented in
FIGS. 5 (control), 6 (cholesterol), 7 (calcium stearate) and 8
(calcium phosphate). The devices shown in the Figures had been
irradiated; the results with non-irradiated devices were
substantially similar.
EXAMPLE 6
Following the procedures of Example 1, 1.times.1 cm square devices,
0.5 mm thick, were made having the following composition: 60 wt %
poly(lactic-glycolic) copolymer ("PLGA") (Resomerl 503, Boehringer
Ingelheim; 50:50 lactic acid:glycolic acid; intrinsic viscosity
0.4.+-.10%; approx. 30,000 MW), 5 wt % lysozyme, 15 wt % lactose
and 20 wt % hydrophobic excipient. The hydrophobic excipients
tested were cholesterol, calcium stearate and calcium phosphate.
Control devices were composed of 75 wt % PLGA (Resomer.RTM. 503), 5
wt % lysozyme and 20 wt % lactose. Certain of the devices were
irradiated (.beta.-irradiation) at 2.5 megarad. The in vitro
release of lysozyme through human cadaver skin was determined (n=3
devices) and the percent release of the various devices is
presented in FIGS. 9 (control), 10 (cholesterol), 11 (calcium
stearate) and 12 (calcium phosphate). The devices shown in the
Figures had been irradiated; the results with non-irradiated
devices were substantially similar.
* * * * *